Screening tumor specificity targeted by arnicolide D, the active compound of Centipeda minima and molecular mechanism underlying by integrative pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Herb-derived anti-tumor agents, such as paclitaxel and vincristine, exert significant but varied effectivenesses towards different cancer types. Similarly, Centipeda minima (CM) is a well-known traditional Chinese medicine that has been used to treat rhinitis, relieve pain and reduce swelling, and recently found to exert overwhelming anti-tumor effects against breast cancer, colon cancer, and nasopharyngeal carcinoma with different response rates. However, what is the optimizing cancer model that benefits most from CM, and what is the specific target underlying still require more exclusive and profound investigations. AIMS OF THE STUDY: This study aimed to explore the dominant tumor model and specific target of CM by integrative pharmacology and biological experiments. MATERIALS AND METHODS: The most predominant and specific cancer types that are sensitive to CM were screened and identified based on a combination network pharmacology and bioinformatics analysis. Compound-target network and protein-protein interaction of CM-related cancer targets were carried out to determine the most abundant active compound. Simultaneously, the priority target responsible for CM-related anti-tumor efficacy was further validated by molecular docking and in vitro experiments. RESULTS: In total, approximately 42% (8/19) of the targets were enriched in prostate cancer (p = 1.25E-09), suggesting prostate cancer would be the most sensitive tumor response to CM-related efficacy. Furthermore, we found that arnicolide D (ARD), the most abundant and representative active compound of CM, could directly bind to Src with binding energy of -7.3 kcal/mol, implying Src would be the priority target responsible for CM-related anti-tumor efficacy. Meanwhile, the results were further validated by solvent-induced protein precipitation (SIP) assay. In addition, PCR and WB results also revealed that either CM or ARD could not influence the gene expression of Src, while significantly decreased its protein expression instead, which further suggested that ARD might markedly shortene the Src protein half-life to promote Src protein degradation, thereby achieving significant anti-prostate cancer efficacy. CONCLUSION: Our findings not only suggest CM as a promising Src-targeting candidate for prostate cancer treatment, but also bring up a strategy for understanding the personalization of herbal medicines by using integrative pharmacology.

The optimal dose of arsenic trioxide induced opposite efficacy in autophagy between K562 cells and their initiating cells to eradicate human myelogenous leukemia.

ETHNOPHARMACOLOGICAL RELEVANCE: Arsenic trioxide (As2O3), a main component of arsenolite which is a common traditional Chinese medicine (TCM) wildly used as a therapeutic agent for more than 2400 years in china, has been accepted as a standard treatment for the patients with acute promyelocytic leukemia (APL) based on the principle in TCM of "using a poison to fight against other poisons or malignancy illnesses". However, it remains unknown that which mechanism is actually responsible for the therapeutic effects against these blood malignancies. AIM OF THE STUDY: The purpose of this study was to explore the actual mechanism that ATO exerts its effects in K562 cells and their initiating cells (K562s). MATERIALS AND METHODS: K562s cells were separated and enriched for CD34+/CD38- cells using magnetic microbeads. Cell proliferation was determined by incorporation of BrdU. Cell apoptosis was evaluated by Annexin-V binding and PI uptake. Autophagy was estimated by acridine orange and immunofluorescence staining of LC3-B and p62. MC colonic formation was used to examine cell self-renew. ROS generation inside living cells was measured by DCFH-DA. Cell differentiation was assessed by the benzidine staining. The SA-ß-gal assay was used to detect cell senescence. Protein expression was examined by western blotting and immunohistochemical staining. RESULTS: K562s cells were stronger in self-renew and resistance to ATO cytotoxicity and starvation-induced apoptosis than K562 cells. Unexpectedly, we found that ATO at a dose of 0.5µM which had no effect on cell proliferation resulted in maximum suppression on self-renew in both cells and maximum starvation-induced apoptosis in K562s cells but minimum starvation-induced apoptosis in K562 cells. Next, we found that ATO no more than 0.5µM selectively induced K562s cell differentiation indicated by benzidine staining, γ-globin and CD235a expression. More importantly, we found that ATO no more than 0.5µM led to opposite efficacy in autophagy between K562 and K562s cells, and the opposite autophagy could induced late-phase senescence in both cells. Finally, we used the optimal dose of ATO to eradicate leukemia cells and obtained a satisfied therapeutic outcomes in vivo. CONCLUSIONS: Our results suggest that the used dose of ATO may determine the fate of cell differentiation senescence or malignant transformation, and the optimal dose of ATO induced opposite efficacy in autophagy between K562 cells and their initiating cells and ultimately leads both cells to late-phase senescence.

Oral kanglaite injection (KLTI) attenuates the lung cancer-promoting effect of high-fat diet (HFD)-induced obesity.

Obesity is a risk factor for cancer and cancer-related mortality, however, its role in lung cancer progression remains controversial. This study aimed to assess whether high-fat diet (HFD)-induced obesity promotes lung cancer progression and whether the promotion can be decreased by Kanglaite injection (KLTI). In vivo, HFD-induced overweight or obesity increases the lung carcinoma incidence and multiplicity in a urethane-induced lung carcinogenic model and cancer-related mortality in a LLC allograft model by increasing oxidative stress and cellular signaling molecules including JAK, STAT3, Akt, mTOR, NF-κB and cyclin D1. These changes resulted in increases in vascular disruption and the lung water content, thereby promoting lung epithelial proliferation and the epithelial-mesenchymal transition (EMT) during carcinogenesis. Chronic KLTI treatment substantially prevented the weight gain resulting from HFD consumption, thereby reversing the metabolic dysfunction-related physiological changes and reducing susceptibility to lung carcinogenesis. In vitro, KLTI significantly suppressed the proliferation and induced apoptosis and differentiation in 3T3-L1 preadipocyte cells and attenuated endothelial cell permeability in HUVECs. Our study indicates that there is a potential relationship between obesity and lung cancer. This is the first study to show that obesity can directly accelerate carcinogen-induced lung cancer progression and that KLTI can decrease the lung cancer-promoting effect of HFD-induced obesity.